A number of patents and publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.
Throughout this specification, including the claims which follow, unless the context requires otherwise, the word “comprise,” and variations such as “comprises” and “comprising,” will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a pharmaceutical carrier” includes mixtures of two or more such carriers, and the like.
Ranges are often expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about,” it will be understood that the particular value forms another embodiment.
This disclosure includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Alzheimer's Disease
The current licensed treatments for Alzheimer's disease (AD) improve the symptoms that people experience but do not alter the progression of the underlying disease changes in the brain. Most of the attempts to develop new treatments have focused on altering deposits of the amyloid protein in the brain, but despite more than a decade of intensive research this has still not yielded any new therapies in the clinic.
The only currently approved medications for the treatment of AD are two groups of drugs, acetylcholinesterase inhibitors (e.g., Aricept™) and non-competitive NMDA receptor blockers (e.g., Memantine′), which give significant symptomatic improvement but do not fundamentally prevent or alter disease progression.
Recent research has concentrated on the mis-processing of the amyloid precursor protein (APP) and overproduction amyloid β(Aβ), as the central causative substrates in the disease process and the main treatment target. However, despite considerable effort and research over more than a decade, these treatments have not yet translated into treatments in the clinic.
The inventors have now determined the importance of RARα signalling in processing the APP into the non-amyloidic pathway, and a key role of this pathway in modulating neuronal survival.
Retinoic Acid Receptors
The retinoic acid receptor (RAR) is a type of nuclear receptor which is activated by both all-trans retinoic acid and 9-cis retinoic acid. There are three retinoic acid receptors, known as RARα, RARβ, and RARγ.
The inventors' studies have highlighted a specific retinoic acid receptor, (RAR)α, as a novel and exciting target for the development of new treatments. This receptor has two potential mechanisms of action; it regulates amyloid deposits in the brain and also plays a key role in the survival of neurons.
The pathological hallmarks of Alzheimer's disease (AD) are the presence of senile plaques containing amyloid β(Aβ) peptide and the formation of neuronal tangles in the cerebral cortex. In addition, 90% of AD patients have amyloid β deposits in their cerebral blood vessels (see, e.g., Vinters, 1987). Recently it has been shown that in AD there are genetic linkages to the disease which are close to genes involved in the retinoid signalling pathway (see, e.g., Goodman and Pardee, 2003). This is mediated by retinoic acid receptors (RARs) and retinoid X receptors (RXRs), both of which have three types α, β, and γ and various isoforms (see, e.g., Bastien and Rochette-Egly, 2004). Transcription occurs when the small lipophilic molecule, retinoic acid (RA) binds to an RAR/RXR heterodimer which then binds to retinoic acid response elements (RAREs) located in the regulatory regions of target genes (see, e.g., Bastien and Rochette-Egly, 2004).
Vitamin A deficiency in rats leads to Aβ deposits in the brain vasculature and a down-regulation of RARα in their cortical neurons; the same receptor deficit is found in the cortices in pathology samples of AD (see, e.g., Corcoran et al., 2004). In addition, vitamin A deficiency produces spatial learning and memory impairments and this cognitive decline, which is a symptom of AD, can be reversed by normalization of brain retinoid signalling (see, e.g., Fischer et al., 1989; Cocco et al., 2002). Similarly, in aged mice, there is a loss of retinoid signalling in the brain and cognitive decline and this can also be reversed by supplementing their diet with retinoids (see, e.g., Etchamendy et al., 2001). Also, vitamin A deficiency in mice can lead to a loss in hippocampal synaptic plasticity, which can be reversed by the addition of retinoids to the diet (see, e.g., Misner et al., 2001).
It has also been shown that the amyloid precursor protein (APP), which gives rise to amyloid β protein, can be differentially spliced depending on the concentration of RA (see, e.g., Pan et al., 1993). The APP can be cleaved into Aβ40 and Aβ42 by β and γ secretases (see, e.g., Selkoe, 2001). Alternatively, APP can be cleaved by a secretases into a soluble neuroprotective fragment (see, e.g., Annaert and De, 2000). Disintegrin-metalloproteinases (ADAMS) have been shown to act as α secretases (see, e.g., Lammich et al., 1999; Endres et al., 2005), and one of these (ADAM10) has been shown to be regulated by RA (see, e.g., Endres et al., 2005) and this appears to be direct as the promoter of this gene contains an RARE (see, e.g., Prinzen et al., 2005).
Other consistent aspects of AD are defects in the levels of the neurotransmitter, acetylcholine, which is produced by cholinergic neurons. In AD, there is a loss of the cholinergic markers choline acetyltransferase (chAT), which synthesises acetylcholine and acetylcholinesterase (Ache); Ache breaks down acetylcholine, and subsequently causes the loss of cholinergic neurons themselves (see, e.g., Coyle et al., 1983; Perry et al., 1992; Geula et al., 1998; Ladner and Lee, 1998; Talesa, 2001). It is the loss in cholinergic function that leads to the memory deficits in AD (see, e.g., Collerton, 1986; DeKosky et al., 1992; Bierer et al., 1995; Fischer et al., 1989). RA can also increase chAT expression (see, e.g., Cervini et al., 1994; Berrard et al., 1995; Bejanin et al., 1994).
The inventors' have now shown that RARα agonists are likely to be useful in the treatment of AD. They prevent neuronal cell death in the presence of Aβ42; in culture, they up-regulate chAT, down-regulate APP and increase the expression of ADAM10. In vivo, the inventors' have shown that feeding RARα agonists to Tg2576 mice (which overexpresses the Swedish mutation of the human APP leading to amyloid β deposits and cognitive decline) results in a significant reduction in the levels of both Aβ40 and Aβ42. Studies demonstrating these findings are described in more detail in the Examples below.
Certain aryl-amido-aryl compounds are known in the art.
Teng et al., 1997 (U.S. Pat. No. 5,663,357) describes certain compounds which apparently have retinoid-like biological activity. All of the compounds exemplified therein (see Table 1, spanning column 6 and 7 therein) have the following formula, in which the ring that is opposite the ring bearing the carboxylic acid group has two tert-butyl substituents.

Shudo, 1987 (U.S. Pat. No. 4,703,110) describes certain compounds which apparently are useful for diagnosis of leukemia types, the treatment of dermatological disorders, and as differentiation-inducing agents for neoplastic cells. Among the compounds exemplified therein (see Tables 1 and 2 spanning columns 8 to 12 therein) are compounds of the following formula, wherein —X— is an amide linkage (see, e.g., the last few compounds in Table 1, and compounds 15-40, 64, 65, 67, and 68 in Table 2). However, in each case, the substituents R1, R2, R3, R4, and R5, when not hydrogen, are alkyl (e.g., -Et, -iPr, -tBu), cycloalkyl (e.g., cyclohexyl), or together form a ring fused to the parent phenyl ring.

Shudo et al., 1996, (U.S. Pat. No. 5,525,618) describes certain compounds which apparently are useful in osteopathic treatment. The following compounds are shown in Table 1 (see columns 8 to 9 therein).

Kato et al., 1992 (EP 0 515 684 A1) describes compounds according to the following general formula. These compounds are said to be useful in treating arteriosclerosis, peptic ulcer, cancer, ischemic organ disease, inflammation and pulmonary silicosis.

Of the numerous compounds described therein, Compound 132 on page 59 has the structure given below.

Mizukoshi et al., 1986 (JP 61-233678 A) describes compounds useful as anti-ulcer agents. Compound 1849-89-4 therein has the structure shown below.

Albright et al., 1998 (U.S. Pat. No. 5,849,735) describes tricyclic compounds of the following general formula. These compounds are said to exhibit in vivo vasopressin antagonist activity and antagonist activity at oxytocin receptors, and to be useful in treating conditions where decreased vasopressin levels are desired, such as in congestive heart failure, in disease conditions with excess renal water reabsorption and in conditions with increased vascular resistance and coronary vasoconstriction.

Additionally, the document includes, as reference example 65 (see column 53 therein), a compound having the structure shown below, without attributing any particular activity to the compound.

Schmidt et al., 1975 (GB 1 409 689) describes compounds referred to as “new penicillin compounds”, which are said to be suitable for treating bacterial infections. Additionally, 4-(3,4,5-trimethoxybenzoylamino)-benzoic acid is mentioned as a precursor compound (for compound 22; see page 35 therein). This precursor compound has the structure shown below.

Coppola et al., 2005 describes compounds said to have activity as inhibitors of 11β-HSD1, and suggests that the compounds may “serve as useful tools to study the effect of 11β-HSD1 inhibition in animal models of diabetes, dyslipidemia and obesity”. Of the compounds described in the document, compound 9a has the structure shown below.
